Phospholipids are phosphate diester compounds, naturally found in the cell membrane, in which one of the alcohol residues is generally a glycerol derivative, and the other is a derivative of a different alcohol which may include a non-ionic, cationic or even an anionic functionality. Phospholipid and phospholipid analogues are of increasing interest, for example to impart the useful properties of biocompatibility, haemocompatibility and to influence the interaction of surfaces with biomolecules such as proteins or enzymes.
Our previous disclosures such as EP-A 0032622, EP-A-0157469, EP-A-0555295, EP-A-0601041, EP-A-0593561, EP-A-00639989, WO-A-9416748 and WO-A-9416749 describe various synthetic zwitterionic compounds including phospholipid analogues and their application in devices having biocompatible and haemocompatible surfaces. The present invention extends this methodology to new polymer systems comprising monomers and macromers produced by a Michael-type addition.
It is well known in the literature that amines undertake nucleophilic attack on the a, unsaturated carbonyl of an acrylate functionality, resulting in a Michael-type 1,4-adduct (Recent stereoselective synthetic approaches to -amino acids. Cole, Derek C., Tetrahedron (1994), 50(32), 9517-82).
This technology has been applied in the preparation of a range of curable coatings (Addition products, radiation-curable surface coating compositions based on the addition products, and their use for wood coating and paper coating, Hintze-Bruning, Horst; Cibura, Klaus; Baltus, Wolfgang, U.S. Pat. No. 5,792,827; High-solids coatingsxe2x80x94formulation aspects. Nowak, Michael T. USA. High Solids Coat. (1982), 7(3), 23-8) or resins (Curing agents for liquid epoxy resins, and curable polymer compositions containing them. Shiono, Kenji; Suzuki, Takehiro. JP 09291135; A process for preparation of room-temperature-curable resins. Furukawa, Hisao; Kawamura, Jo., EP 274112).
It has also been used extensively in polymer science, for example, to produce a variety of polymer hybrids (Conductive wire coating based on a curable acrylate-modified amine-terminated polyamide. Frihart, Charles R.; Kliwinski, Joseph. WO 9724191; A polylactone having amino groups, its preparation, and coating and printing ink compositions containing it. Matsui, Hideki, EP 713894; Grafting of amine-functional polymers onto functionalized oxymethylene polymers and the resulting graft polymers thereof. Auerbach, Andrew B.; Broussard, Jerry A.; Yang, Nan L.; Paul, James L. EP 400827) or to build dendrimer structures (Dense star polymers. Tomalia, Donald A.; Dewald, James R. WO 8402705).
It can also be used to functionalise biologically active amine-bearing compounds (A synthesis of N-substituted-alanines: Michael addition of amines to trimethylsilyl acrylate. Kwiatkowski, Stefan; Jeganathan, Azhwarsamy; Tobin, Thomas; Watt, David S. Maxwell H. Synthesis (1989), Issue 12, 946-9). In EP-A-0933399 polysiloxane compounds having at least one aminoalkyl substituent on a silicon atom are cross-linked by reaction with di- or oligo-acrylate compounds, optionally in the presence of other acrylic compounds. One example of a substituted acrylic compound which could be incorporated is N,N-dimethyl-N-methacryloxyethyl-N-3-sulphopropyl)-ammonium betaine.
In some of the prior art the reaction may be carried out with either acrylate or methacrylate, although the former is generally preferred in the literature on reactivity grounds. The reaction proceeds usually without catalysis, although there are reports of catalysts to promote solely 1,4 addition in good yields (Catalysis of the specific Michael addition: the example of acrylate acceptors. Cabral, Jose; Laszlo, Pierre; Mahe, Loic; Montaufier, Marie Therese; Randriamahefa, S. Lalatiana., Tetrahedron Lett. (1989), 30(30), 3969-72).
The present invention relates to new polymers, processes for producing them, processes for coating surfaces with them and polymer compositions. The invention also provides new prepolymers and processes for their production.
Such polymers are particularly useful in the manufacture or coating of devices with medical applications such as blood contacting devices, contact and intraocular lenses, and other devices which are used in contact with protein-containing or biological fluids.
The present invention provides a zwitterion containing Michael-type adduct having the formula (I) 
wherein
Z is a zwitterionic group;
X is an electron withdrawing group selected from the group consisting of carbonyl and sulphone groups, sulphonium and phosphonium salts;
R is selected from the group consisting of linear and branched alkanediyl, alkenediyl, alkynediyl, cycloalkanediyl, cycloalkenediyl, cycloalkynediyl, arylene, alkarylene, aralkylene, alkoxyarylene, alkoxyalkyl, oligo(alkoxy)alkyl, mono- and di-alkylaminoalkyl N-arylaminoalkyl, N-aryl-N-alkylaminoalkyl;
R1 and R2 are independently selected from hydrogen and C1-C12 alkyl groups;
A is O or NR6, where R6 is selected from the group consisting of hydrogen and C1-6 alkyl.
R3 is selected from the group consisting hydrogen, linear and branched alkyl, alkenyl, and alkynyl groups, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloaryl, haloalkyl, aryl, alkaryl, aralkyl, alkoxyaryl, alkoxyalkyl, oligoalkoxyalkyl, aminoalkyl, mono- and di-alkylaminoalkyl, arylaminoalkyl, N-aryl-N-alkylaminoalkyl and -aminoaryl, acyloxy, acyloxyalkyl, acylaminoalkyl, N-diacyl-iminoalkyl groups, mono- and di-alkylaminocarbonyl, organosilyl, arylamino carbonyl, aryl(alkyl)amino carbonyl, and organosiloxyl groups and any of the above groups substituted with
a reactive group,
a group NHCOOR5 in which R5 is selected from the group consisting hydrogen, linear and branched alkyl, alkenyl, and alkynyl groups, cycloalkyl, cycloalkenyl, cycloalkynyl, haloaryl, haloalkyl, aryl, alkaryl, aralkyl, alkoxyaryl, alkoxyalkyl, oligoalkoxyalkyl, aminoalkyl, mono- and di-alkylaminoalkyl, arylaminoalkyl, N-aryl-N-alkylaminoalkyl and aminoaryl, acyloxyalkyl, acylaminoalkyl, N-diacyl-iminoalkyl groups, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxyaryl, hydroxyalkoxyalkyl and hydroxy(oligoalkoxy)alkyl;
a group xe2x80x94NHCONR7R8 in which R7 and R8 are selected from the group consisting hydrogen, linear and branched alkyl, alkenyl, and alkynyl groups, cycloalkyl, cycloalkenyl, cycloalkynyl, haloaryl, haloalkyl, aryl, alkaryl, aralkyl, alkoxyaryl, alkoxyalkyl, oligoalkoxyalkyl, aminoalkyl, mono- and di-alkylaminoalkyl, arylaminoalkyl, N-aryl-N-alkylaminoalkyl and aminoaryl, acyloxyalkyl, acylaminoalkyl, N-diacyl-iminoalkyl groups, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxyaryl, hydroxyalkoxyalkyl and hydroxy(oligoalkoxy)alkyl; or
a polymeric moiety; and
R4 is selected from the group consisting hydrogen, linear and branched alkyl, alkenyl, and alkynyl groups, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloaryl, haloalkyl, aryl, alkaryl, aralkyl, alkoxyaryl, alkoxyalkyl, oligoalkoxyalkyl, aminoalkyl, mono- and di-alkylaminoalkyl, arylaminoalkyl, N-aryl-N-alkylaminoalkyl and -aminoaryl, acyloxy, acyloxyalkyl, acylaminoalkyl, N-diacyl-iminoalkyl groups, mono- and di-alkylaminocarbonyl, organosilyl, arylamino carbonyl, aryl(alkyl)amino carbonyl, and organosiloxyl groups and any of the above groups substituted with
a group II 
in which the groups R, R1, R2. R4, Z and A are the same as in (I);
a group III 
in which
A1 is O or NR13 where R13 is hydrogen or C1-4 alkyl;
X1 is an electron withdrawing group selected from carbonyl, sulphonyl, sulphonium and phosphonium groups;
R12 is H or C1-6 alkyl;
R10 and R11 are independently selected from H and C1-4 alkyl; and
R9 is optionally substituted alkyl or aryl;
a reactive group; or.
a polymeric moiety.
In the definition of R3, and R4, and any of the groups below any alkyl group or moiety is preferably C1-18 alkyl, any alkenyl group or moiety is preferably C2-18 alkenyl, any alkynyl group or moiety is preferably C2-12 alkynyl, any aryl group or moiety is preferably C6-24 aryl, any alkaryl group or moiety is preferably C7-24 alkaryl and any aralkyl group or moiety is preferably C7-24 aralkyl, any cycloalkyl group or moiety is preferably C4-24 cycloalkyl, any cycloalkenyl group or moiety is preferably C5-24 cycloalkenyl, any cycloalkynyl group or moiety is preferably C5-24 cycloalkynyl.
The zwitterionic group Z preferably has the general formula (IV) 
in which the moieties A2 and A3, which are the same or different, are xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94 or a valence bond, preferably xe2x80x94Oxe2x80x94, and W+ is a group comprising an ammonium, phosphonium or sulphonium cationic group and a group linking the anionic and cationic moieties which is preferably a C1-12-alkanediyl group,
preferably in which W+ is a group of formula
xe2x80x94W1xe2x80x94N+R143, xe2x80x94W1xe2x80x94P+R153, xe2x80x94W1xe2x80x94S+R152 or xe2x80x94W1xe2x80x94Het+in which: 
W1 is alkanediyl of 1 or more, preferably 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, which group W1 optionally contains one or more fluorine substituents and/or one or more functional groups; and
either the groups R14 are the same or different and each is hydrogen 2 D or alkyl of 1 to 4 carbon atoms, preferably methyl, or aryl, such as phenyl, or two of the groups R14 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R14 together with the nitrogen atom to which they are attached form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R14 is substituted by a hydrophilic functional group, and
the groups R15 are the same or different and each is R14 or a group OR14, where R14 is as defined above; or
Het is an aromatic nitrogen-, phosphorus- or sulphur-, preferably nitrogen-, containing ring, for example pyridine.
Most preferably the zwitterionic group of the formula (IV), has the general formula (V): 
where the groups R16 are the same or different and each is hydrogen or C1-4 alkyl, and m is from 1 to 4, preferably 2. Preferably the groups R16 are the same and are preferably methyl.
Alternatively, the zwitterionic group may be a betaine group (ie. in which the cation is closer to the backbone), for instance a sulpho-, carboxy- or phospho-betaine. A betaine group should have no overall charge and Is preferably therefore a carboxy- or sulphobetaine. If it is a phosphobetaine the phosphate terminal group must be a diester, i.e., be esterified with an alcohol. Such groups may be represented by the general formula (IV) 
in which A4 is a valence bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94, preferably xe2x80x94Oxe2x80x94;
V is a carboxylate, sulphonate or phosphate diester(monovalently charged) anion;
R17 is a valence bond (together with A4) or alkanediyl, C(O)alkylene- or xe2x80x94C(O)NHalkylene preferably alkanediyl, and preferably containing from 1 to 6 carbon atoms in the alkanediyl chain;
the groups R18 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms or the groups R18 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 atoms; and
R19 is alkyanediyl of 1 to 20, preferably 1 to 10, more preferably 1 to 6 carbon atoms.
One preferred sulphobetaine monomer has the formula (VII) 
where the groups R20 are the same or different and ach is hydrogen or C1-4 alkyl and s is from 2 to 4.
Preferably the groups R20 are the same. It is also preferable that at least one of the groups R20 is methyl, and more preferable that the groups R20 are both methyl.
Preferably s is 2 or 3, more preferably 3.
Alternatively the zwitterionic group may be an amino acid moiety in which the alpha carbon atom (to which an amine group and the carboxylic acid group are attached) is joined through a linker group to the backbone of the biocompatible polymer. Such groups may be represented by the general formula (VIII) 
in which A5 is a valence bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94, preferably xe2x80x94Oxe2x80x94,
R22 is a valence bond (optionally together with A5) or alkanediyl, xe2x80x94C(O)alkylene- or xe2x80x94C(O)NHalkylene, preferably alkanediyl and preferably containing from 1 to 6 carbon atoms; and
the groups R21 are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or two or three of the groups R21, together with the nitrogen to which they are attached, form a heterocyclic ring of from 5 to 7 atoms, or the three group R21 together with the nitrogen atom to which they are attached form a fused ring heterocyclic structure containing from 5 to 7 atoms in each ring.
X is preferably a carbonyl group.
A is preferably 0
R1 is preferably hydrogen.
R2 is preferably methyl, or, more preferably, hydrogen.
R is preferably C2-6-alkanediyl.
R3 is preferably hydrogen, or is an optionally substituted alkyl aminocarbonyl or arylaminocarbonyl group.
In a preferred embodiment R3 is a hydrog n atom or comprises a reactive group. Reactive groups include, for example, groups containing an ionic group or a site of unsaturation that is capable of forming a covalent bond with another group or to a substrate. Alternatively the reactive group may increase the ability of the adduct to physisorb or chemisorb to another group or to a substrate relative to the ability of the adducts to physisorb or chemisorb exclusive of the reactive group.
Preferred substrates include, for example, silicones, polyurethanes, polyalkacrylates, polystyrenes, polycarbonates, polyesters and metals (particularly stainless steel).
Other groups with which the reactive group may bond, physisorb or chemisorb to include, for example, another adduct (I) or polymer formed by polymerisation of adduct (1), polymers having desirable physical or mechanical properties, drugs, ligands or biological molecules such as enzymes or heparin.
Where R3 comprises a reactive group, it preferably comprises at least one group selected from the group consisting of isocyanate, organosilane and (meth)acryloyloxy.
Most preferably a group R3 which contains a reactive group is an cycloalkylaminocarbonyl, arylaminocarbonyl, or alkylaminocarbonyl group containing an isocyanate substituent.
R4 is preferably, other than hydrogen, more preferably an organopolysiloxane group, an oligoalkoxyalkyl group, an organosilyl group or a C6-24 alkyl group.
An organosiloxyl group Y utilised in the present invention, for example as R4, preferably has the formula (IX) 
in which at least one of the groups R23, R24 and R25 is a divalent moiety selected from the group consisting of a valence bond, C1-12 alkanediyl, C2-12 alken diyl and C2-12 alkynediyl and is covalently bonded to the nitrogen atom of adduct (I) and the remaining groups R23, R24 and R25 each represent a monovalent moiety independently selected from the group consisting of branched and straight C1-12 alkyl, C6-18 aryl, C6-18 alkaryl, C6-18 aralkyl, C2-12 alkenyl and C2-12 alkynyl any of which may be substituted by a primary, secondary or tertiary amine group or by a group III as defined in claim 1; and
n is 0-300.
Preferably IX has a molecular weight of 300-20000, for instance 500-10000, more preferably 1000-7000, most preferably 3000-6000.
Preferably R23 and R25 are selected from methanediyl, ethanediyl, propanediyl and butanediyl, and are both covalently bound to the nitrogen atom of individual adducts (I).
Alternatively, or in addition to both R23 and R25 being connected to adducts (1), one or more of the groups R24 may comprise a xe2x80x94NR262, substituent where each R26 is independently selected from hydrogen or C1-6 alkyl and aryl, or a substituent of the formula III as defined above.
In preferred embodiments adduct (I) has one of the formula (X), (XI), (XII), (XIII), or (XIV) 
wherein each of the of the groups R27 is independently selected from the group consisting of C1-6 alkyl, C6-18, aryl, C6-18 alkyl, C6-18 alkaryl, and C2-6 alkenyl, preferably C1-6 alkyl, most preferably methyl or ethyl;
the or each R28 is independently selected from the group consisting of C1-6 alkanediyl, C2-6 alkendiyl and C2-6 alkynediyl, preferably C1-6 alkanediyl;
R31 is selected from the same groups as R27 or is a group R28 NH2;
R32 is selected from the same groups as R27 or is a group R28 NH2 or a group R28 NH(CH2)2COO(CH2)2 Z or a group xe2x80x94R28N(CONHR30)CH2CH2COO(CH2)2Z;
R29 is selected from the group consisting of hydrogen, C1-6 alkyl, C6-18 aryl, C6-18 aralkyl, C2-6 alkenyl, C6-18 alkaryl, preferably hydrogen or C1-4alkyl;
each R30 is independently selected from the group consisting hydrogen, linear and branched alkyl, alkenyl, and alkynyl groups, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloaryl, haloalkyl, aryl, alkaryl, aralkyl, alkoxyaryl, alkoxyalkyl, oligoalkoxyalkyl, aminoalkyl, mono-, di- and tri-alkylaminoalkyl, arylaminoalkyl; N-aryl-N-alkylaminoalkyl and -aminoaryl, acyloxy (including alkenoyloxy), acyloxyalkyl (including alkenoyloxyalkyl), acylaminoalkyl, N-diacyl-iminoalkyl groups, alkylaminocarbonyl, organosilyl and organosiloxyl groups and any of the above groups substituted with a zwitterionic group Z or an isocyanate group;
n is an integer of 1 to 500;
p is an int ger of 1 to 50;
r is an integer of 1 to 50; and
s is 0 or 1 (preferably 1).
The formula (XIII) and (XIV) are not intended to represent the specific order within the organosiloxane backbone of the groups [xe2x80x94Oxe2x80x94SiR272], [xe2x80x94Oxe2x80x94SiR32R28 . . . ] and [xe2x80x94Oxe2x80x94SiR31(R28 . . . )], and in fact these groups can be randomly or specifically ordered within the backbone.
Most preferably all groups R27, R31 and R32, are methyl and R28 is selected from 1,2-ethanediyl, 1,3-propanediyl and 1,4-butanediyl.
Alternatively, R4 may comprise a polyoxyalkylene group having the formula (XV) 
wherein each group R33 is independently selected from the group consisting of hydrogen, C1-6 alkyl C6-18 aryl, C6-18 aralkyl, C6-18 alkaryl and C2-6 alkenyl;
each group R34 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C6-18 aryl, C6-18 aralkyl, C6-18 alkaryl and C2-8 alkenyl;
R35 is a divalent moiety selected from the group consisting of a valence bond, C1-6 alkanediyl, C6-18 arylene, C6-18 aralkylene, C2-8alkenediyl, mono-, di- and tri-alkylaminoalkyl, arylaminoalkyl, arylaminoaryl, N-aryl-N-alkylaminoalkyl and -aminoaryl;
R36 is a divalent moiety selected from the same groups as R35 or is a monovalent moiety selected from the same groups as R33, aminoalkyl and aminoaryl, and alkyl and aryl groups substituted by groups of general formula II or III as defined in claim 1;
a is 0 or an integer in the range 1-10,
b is 0 or an integer of in the range 1-500; and
(XV) has a formula weight of 100-10000.
Each group R34 is preferably selected from hydrogen and C1-4 alkyl, and is most preferably methyl or, most preferably hydrogen. For instance one of the groups R34 may be a methyl group and the rest hydrogen, but most preferably all are hydrogen.
Preferably group XV has a formula weight in the range 50-20,000.
In a further preferred embodiment, adduct (I) has the formula (XVI), (XVII) or (XVIII) 
wherein each group R33 is independently selected from the group consisting of hydrogen, C1-4 alkyl, C6xcx9caryl, C6-18 aralkyl, and C6-18 alkaryl;
each group R37 is independently selected from the group consisting of hydrogen, C1-4 alkyl, C6-18 aryl, C6-18 aralkyl, and C6-18 alkaryl;
each group R34 is independently selected from the group consisting of hydrogen, C1-4 alkyl, C6-18 aryl, C6-18 aralkyl, and C6-18 alkaryl;
c is 0 or an integer in the range 1 to 10;
R38 is selected from the group consisting of hydrogen, C1-4alkyl, C6-18 aryl, C6-18 aralkyl, C6-18 alkaryl, and C2-6 alkenyl; and
each R39 is independently selected from the group consisting of hydrogen, linear and branched alkyl, alkenyl, and alkynyl groups, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloaryl, haloalkyl, aryl, alkaryl, aralkyl, alkoxyaryl, alkoxyalkyl, oligoalkoxyalkyl, aminoalkyl, mono, di- and tri-alkylaminoalkyl, arylaminoalkyl, N-aryl-N-alkylaminoalkyl and -aminoaryl, acyloxy (including alkenoyloxy), acyloxyalkyl (including alkenoyloxyalkyl), acylaminoalkyl, N-diacyl-iminoalkyl groups, alkylaminocarbonyl, organosilyl and organosiloxyl groups and any of the above groups substituted with a zwitterionic group Z or an isocyanate group.
Preferably each group R34 is selected from propyl, ethyl, methyl and hydrogen and are preferably all the same, more preferably hydrogen.
R36 is preferably hydrogen.
One preferred organosilane group as R4 or, less preferably, R3, has the general formula (XIX) 
wherein each R47 is selected from the group consisting of hydrogen, branched and straight C1-12 alkyl, C6-18 aryl, C6-18 alkaryl, C6-18 aralkyl, C2-12 alkenyl and C2-12 alkynyl;
R40 is selected from the group consisting of a valence bond, branched and straight chain C1-12 alkanediyl, straight and branched C2-12 alkenediyl and straight and branched C2-12 alkynediyl; and
(X) is connected to the N atom of (I) through R40.
The present invention additionally provides a method for the production of an adduct by the Michael-type addition of a compound having the formula (XX) 
with an amine reagent having the formula (XXI)
H2NR41xe2x80x83xe2x80x83(XXI) 
to form a zwitt rion containing compound having the formula (XXII) 
wherein
Z is a zwitterionic group;
A is O or NR6 in which R6 is hydrogen or a C1-4 alkyl group;
X is an electron withdrawing group selected from the group consisting of carbonyl and sulphone groups, sulphonium and phosphonium salts;
R is selected from the group consisting of linear and branched alkanediyl, alkenediyl, alkynediyl, cycloalkanediyl, cycloalkenediyl, cycloalkynediyl, arylene, alkarylene, aralkylene, alkoxyarylene, alkoxyalkylene, oligoalkoxyalkylene, mono- or di-alkylaminoalkyl, N-arylamino alkylene, is N-aryl-N-alkylaminoalkylene,
R41 is selected from the group consisting hydrogen, linear and branched alkyl, alkenyl and alkynyl groups, cycloalkyl, cycloalkenyl, cycloalkynyl, haloaryl, haloalkyl, aryl, alkaryl, aralkyl, hydroxyalkyl, hydroxyaryl, alkoxyaryl, alkoxyalkyl, oligoalkoxyalkyl, acyloxyalkyl, organosilane and organosiloxane groups any of which may be substituted by a group selected from amino, N-alkyl amino, N,N-dialkylamino, N-aryl-N-alkylamino and N-acylamino groups; and
R1 and R2 are independently selected from hydrogen and C1-C12 alkyl groups.
R1 and R2 are preferably selected from hydrogen or C1-C4 alkyl groups most preferably both are hydrogen.
The structure is not intended to represent that when R1 and R2 are not both hydrogen atoms that are in a cis-configuration about the double bond and in fact they may be trans.
A, Z, R and X have the same preferred definitions as in the adduct of general formula I above.
R41 is preferably the respective group from which the preferred R4 groups described above are derived. Often R41 includes amino substitutions, whereby the second amine group may take part in a reaction with a zwitterionic reagent of the general formula XX.
One mole of amine reagent may react with up to two moles of zwitterionic reagent. Alternatively the primary or secondary amine derived from the amine reagent may be used to crosslink to or otherwise react with a different group or substrate, either by a Michael type addition or an alternative reaction mechanism, for example, nucleophilic addition or substitution. Simultaneously or after the reaction of the zwitterionic reagent and the amine reagent, some of the amine groups of a di- or oligo-amine reagent (that is in which R41 includes one or more amine substituents) may be reacted in a further Michael addition with acrylic reagents of the general formula 
in which
A1 is O or NR13 where R13 is hydrogen or C1-6 alkyl;
X1 is an electron withdrawing group selected from carbonyl, sulphonyl, sulphonium and phosphonium groups;
R12 is H or C1-6 alkyl;
R10 and R11 are independently selected from H and C1-4 alkyl; and
R9 is optionally substituted alkyl or aryl.
By carrying out such a further reaction those amine groups of the amine reagent are converted to groups of the general formula III defined above.
Compound (XXII) may undergo a second reaction with an isocyanate reagent (XXIII)
R42xe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83(XXIII) 
wherein R42 is selected from the group consisting of linear and branched alkyl, alkenyl, and alkynyl groups, alkoxycarbonyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloaryl, haloalkyl, aryl, alkaryl, aralkyl, alkoxyaryl, alkoxyalkyl, oligoalkoxyalkyl, di-alkylaminoalkyl, N-aryl-N-alkylaminoalkyl and acyloxy (including alkenoyloxy), acyloxyalkyl (including alkenoyloxyalkyl), N-diacyl-iminoalkyl groups, organosilane and organosiloxane groups and any of the above groups substituted with a zwitterionic group Z or an isocyanate group, to form a compound having the formula (XXIV) 
in which R43 is the same as R42 or, where R42 comprises an isocyanate group, may be the corresponding group formed by reaction of the isocyanate group with a compound having an active hydrogen atom present in the second reaction mixture a hydroxyl group containing compound or a primary or secondary amine group containing compound).
In a preferred embodiment, R42 comprises a site of unsaturation, most preferably an isocyanate group or an ethylenic group, capable of crosslinking to another compound of general structure (XX), another polymer or group, or alternatively a substrate as defined hereinbefore. Said site of unsaturation may alternatively provide a site at which homo or co-polymerisation of a compound (XXIV) may occur, for example an ethylenically unsaturated group such as alkenoyloxy.
Most preferably the isocyanate reagent is an isocyanate or diisocyanate and is preferably selected from the group consisting of C2-30, aliphatic, C6-30 aromatic and C6-20 alicyclic isocyanates or diisocyanates C4-30 allyl isocyanates, C3-30 isocyanatoalkylacrylates, C5-30 isocyanato alkylmethacrylates, more preferably preferably allyl isocyanate, dimethyl meta-isopropenylbenzylisocyanate, isophorone diisocyanate, hexamethylene diisocyanate, meta-tetramethylxylylene diisocyanate.
In the reaction of amine with zwitterionic reagent in a preferred embodiment of amine reagent group R41 has the general formula XXV 
in which one of the groups R44 or R45 is a divalent moiety selected from the group consisting of a valence bond, C1-12-alkanediyl, C2-12 alkenediyl, C2-12-alkynediyl and the remaining groups R44, R45 and R46 are monovalent moieties independently selected from straight and branched C1-12-alkyl, C2-12 alkenyl, C2-12 alkynyl, C6-24 alkanyl, C6-24 aryalkyl and aryl, any of which groups may be substituted by one or more amino, N-alkylamino, N,N-dialkylamino, N-alkyl-N-arylamino or N-arylamino groups; and
t is 0 to 300.
In such an embodiment preferably R44 is a C2-6 alkanediyl, each of the groups R45 is methyl, R46 is an amino substituted C2-6 alkyl group and n is in the range 5 to 50.
In another preferred embodiment of the process of the invention, in the amine reagent R41 is a group of formula XXVI 
wherein each group R33 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C6-18 aryl, C6-18 aralkyl, C6-18 alkaryl end C2-6 alkenyl; each group R34 is independently selected from the group consisting of hydrogen, C1-4 alkyl, C6-18 aryl, C6-18 aralkyl, C6-18 alkaryl and C2-6 alkenyl;
R35 is a divalent moiety selected from the group consisting of a valence bond, C1-6 alkanediyl, C6-18 arylene, C6-18 aralkylene, C2-6 alkenediyl, mono-, di- and tri-alkylaminoalkyl, arylaminoalkyl, arylaminoaryl, N-aryl-N-alkylaminoalkyl and N-aryl-N-alkylaminoaminoaryl;
R47 is selected from the same groups as R33, or is C1-12 alkyl substituted by an amino, N-alkylamino, N,N-dialkylamino N-arylamino or N-aryl-N-alkylamino group;
u is 0 or an integer in the range 1-10,
v is 0 or an integer of in the range 1-500; and
XXVI has a formula weight of 100-10000.
The two steps of the preferred reaction may be carried out simultaneously separately. Two separate steps are favoured as this allows work up of a characterisable, pure product after the first step.
The first step (reaction of the zwitterionic reagent with the amine reagent) may be performed in a solventless system when one component is able to solubilise the other. Alternatively, an aqueous or organic solvent may be utilised. Preferred organic solvents include alcohols (including hydroxyalkyl(meth)acrylates), chlorinated hydrocarbons, organosulphoxides, alkylamides and ethers.
Where (I) contains an ester linkage, one prerequisite for the Michael addition step is that the solvent in which the reaction occurs is chosen carefully in order to avoid the possibility of transesterification of the ester linkage in the resulting adduct. Transesterifications are acid or base catalysed reactions and it is likely that the basic structure of the secondary amine in the adduct is sufficient to catalyse the convertion. In particular it is found that the use of methanol as a reaction solvent results in a Michael adduct that has been almost exclusively transesterified, producing the methyl ester of the amine. When isopropylalcohol is used instead of methanol, the trans sterification is virtually eliminated with only traces of the transest rifled product being detected. Acidity, nucleophilicity and steric hinderance of the alcohol group are all considerations in determining whether the solvent system used will be suitable for the Michael addition.
The second step of the reaction with the isocyanate may be carried out in a solventless system or in aqueous or organic solvents. Preferably, where isocyanate or diisocyanates are utilised, the reaction is carried out in the absence of water. As the reaction proceeds an organic solvent is usually required. Preferred organic solvents include alcohols (including hydroxyalkyl(meth)acrylate), chlorinated hydrocarbons, organosulphoxides, alkylamides and ethers.
A particularly preferred solvent for the first reaction is isopropanol or hydroxyethylmethacrylate. For the second reaction, the preferred solvents include dimethylsulphoxide, isopropanol, hydroxyethylmethacrylate, tetrahydrofuran, or N-methylpyrrolidone or mixtures thereof.
Scheme 1 shows two reaction routes resulting in particularly preferred products. 
wherein m and ar integers of 10-400.
In both examples (reaction with organosiloxane (B) or polyoxyalkylene) (C)) the first two steps may be carried out separately or concurrently depending on the stoichiometry of the reaction. Preferably the production of (E) or (H) by the zwitterion containing group (A) occurs in one step. The reaction product is preferably recovered and the further step of reaction with a reactive group (in the examples shown, an isocyanate), is carried out.
For example, if a diisocyanate compound is used to functionalise compound (E) or compound (H), this will produce an isocyanate-functionalised oligomer that could form a block in a segmented polyurethane urea.
Scheme 2 illustrates another particularly preferred embodiment of the present invention. Compound (E) (or more generally an intermediate of the general formula (XXII) is reacted with a diisocyanate compound to produce a compound of type (K) having pendant isocyanate groups. This compound can be reacted further with a capping reagent, for example, hydroxyethylmethacrylate or
t-butylaminoethyl methacrylate to produce a methacrylate-terminated oligomer (compounds (L) and (M) in scheme 2, ideal for free-radical polymerisation with other ethylenically unsaturated monomers. This could also be achieved in one step if a zwitterion containing Michael adduct is reacted with an isocyanate bearing unsaturation in some form. Particularly useful are isocyanates such as dimethylmeta-isopropenylbenzylisocyanate, allylisocyanate or methacryloloxyethylisocyanate.
Alternatively, or prior to introduction of a cap, compound K, for example, could be reacted with a similar or dissimilar group E, for example. Another amine (either having undergone or not undergone a Michael addition reaction) may be introduced to react with (K) as another way of adding additional entities with desired physical and/or chemical properties into the molecule. The xe2x80x9coth r aminexe2x80x9d is typically any diamine for which the ratio of diisocyanate is adjusted such that some chain extension of compound (K) occurs, prior to capping the molecule. The addition of the xe2x80x9cotherxe2x80x9d amine is prior to cap addition and may be accompanied by further diisocyanate addition to maintain stoichiometry. 
Materials comprising the adducts described hereinbefore are of particular utility in medical device manufacture.
In particular, organosiloxane containing adducts, or polymers or copolymers produced by their polymerisation have particular utility in the manufacture of contact and intra ocular lenses. They provide high oxygen permeability and biocompatibility within the ocular environment.
Where the amine reagent of the general formula XXI comprises functional groups in addition to the amine functionality, an adduct formed therefrom can provide products that possess utility as graftable coatings. For example, where the amine reagent comprises pendant reactive groups such as alkyl groups substituted with aldehyde or carboxylic acid groups, adducts (or polymers) formed therefrom may be used to graft onto biological tissue bearing lysine moieties. Alternatively, where an amine is functionalised with an organosilane group such as (XIX), this may be used to graft an adduct of the present invention to an organic or inorganic substrate. Compounds and polymers bearing such an organosilane group show particular utility in bonding to metal surfaces.
The presence of the zwitterionic component in a polymer provided by polymerisation of an adduct of the present invention improves the biocompatibility of the material compared with non-zwitterionic containing analogues. If, for example, it is desirable to make biodegradable materials, this could be achieved by the incorporation of a suitably labile chain extender, the degradation product being less toxic to the body than a similar compound not bearing a zwitterionic group. Similarly, wear-debris from a nondegradable implant or contact lens of the materials should also be of less risk than a similar material not bearing a zwitterionic group to the body or ocular environment.
The production of a polymer comprising an adduct of the present invention may be achieved by any known polymerisation method. As described above, this may be achieved by funtionalising the adduct to incorporate a site of unsaturation, thus providing an adduct capable of, for example, free radical polymerisation.
The present invention additionally incorporates compositions comprising adduct(s) of the present invention, and compositions of polymers produced by polymerisation of such an adduct.
The following examples illustrate the working of the present invention.
Starting Materials:
PEG refers to polyethyleneglycol and AEW refers to amine equivalent weight The molecular weight (Mw) of AMS 162 is 4000-5000.
All materials were obtained and purified as described in the examples. (2-acryloyloxyethyl)-2xe2x80x2-(trimethyl-ammoniumethyl) phosphate, inner salt (Acryloyl-phosphorylcholine, APC) was made by a modification of the route described previously by Ishihara et al. (Polym. J., 2(3), 355, 1990):
All glassware was dried thoroughly before use. 2-Chloro-2-oxo 1,3,2 dioxaphospholane (CCP, Avocado Chemical Co.) (68.3 g, 0.48 mol, 1.05 equiv.) was weighed into a 250 ml self-equilibrating dropping funnel and dissolved in xcx9c50 ml of acetonitrile. Hydroxyethyl acrylate (HEA, Aldrich Chemical Co.) (53 g, 0.46 mole) was measured into a 3-neck 2L r.b. flask, fitted with a thermometer (range xe2x88x92100xc2x0 C.-50xc2x0 C.), the dropping funnel, a N2 bubbler and a magnetic stirrer. The HEA was dissolved in 700 ml acetonitrile and cooled to 0xc2x0 C. using a solvent/CO2 bath. Whilst stirring, N,N,Nxe2x80x2,Nxe2x80x2-tetramethylene diamine (TMEDA, Aldrich Chemical Co.) (36 g, 0.24 mol, 1.05 equiv.) were added, followed by the dropwise addition of the CCP solution over a 20 minute period. The reaction mixture went cloudy upon addition of the CCP as the TMEDA.2HCl salt formed. The reaction was left to stir for 2 hours.
The TMEDA.2HCl was filtered off under vacuum and an N2 atmosphere and washed with acetonitrile (xcx9c60 ml). The clear pale yellow solution was collected in a 2L Florentine flask. A solvent/CO2 bath was used to cool the solution to xcx9c0xc2x0 C. before bubbling trimethylamine (TMA, Aldrich Chemical Co.) (81.53, 1.38 mol, 3 equiv.) into the solution, while stirring. The flask was fitted with an air condenser with a balloon attached to the top and stirred at 50xc2x0 C. for 16 hours. Excess TMA was then removed under vacuum via a solvent/CO2 cold trap, using a HCl trap, whilst stirring at 40xc2x0 C. xcx9c300 ml of acetonitrile was removed and white solid product of APC was filtered off under vacuum and N2.
Weight of product collected=93.7 g 73%. 1H NMR (in D2O) confirmed the product had been made (characteristic singlet for xe2x80x94N+(CH3)3@3.15-3.22 ppm, double bond of the acrylate@5.98-6.02 ppm (doublet), 6.19-6.26 ppm (quartet), 6.44-6.48 ppm (doublet)). 31P NMR (in CDCl3) showed a peak@xe2x88x920.53 ppm as expected.